PROJECT SUMMARY Age-related neurodegenerative diseases like Alzheimer?s Disease exhibit a breakdown in neuronal protein homeostasis (proteostasis). The relationship between age-related metabolic dysfunctions and protein aggregation in such diseases remains poorly understood. Elucidating the molecular basis for the age-related loss of proteostasis is expected to inspire new therapeutic approaches, not only for diseases like Alzheimer?s, but more broadly for a wide range of age-related diseases. Increasingly, this promise of ?Geroscience? is being recognized as critical for extending our healthspan. Among the most productive experimental approaches in Geroscience is the use of genetically accessible model systems for the study of longevity. These models have allowed the identification of single gene mutations and of interventions that extend lifespan, highlighting the plasticity of the aging process and suggesting avenues to significantly alter its course. The cellular events impacted by such interventions and causing the lifespan extension, however, remain largely unclear. In many cases, the effect on longevity is associated with changes in proteostasis and metabolism. To understand the relationship between proteostasis and longevity in detail, however, requires an integrated approach that investigates the effects of lifespan extending perturbations on global protein homeostasis and metabolic flux in a well-defined genetic system. Here, the applicants propose such integration by combining the expertise of groups using genetic approaches (Jasper), proteomic and bioinformatic approaches (Schilling and Ghaemmaghami), and metabolomic approaches (Ramanathan) to develop models for protein and metabolic homeostasis in long-lived mutants of Drosophila. Recent technological advances in the field of mass spectrometry have enabled global analyses of protein turnover rates and metabolic flux in complex organisms. Combining these technologies with detailed analysis of lifespan-extending genetic perturbations is expected to provide transformative new insights into molecular changes required for longevity. The aims proposed by the applicants are to (i) assess age-related changes in global protein turnover and metabolic flux, (ii) determine if changes in energy metabolism downstream of the Jun-N-terminal Kinase and Insulin signaling pathways influence protein turnover, and (iii) perform genetic studies to explore the causes of aging and longevity. It is anticipated that combining the strengths of the Drosophila system with state-of-the-art proteomic and metabolomic approaches will significantly accelerate the discovery of fundamental mechanisms influencing physiology and cell function with age, providing new therapeutic avenues for age-related diseases.